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Prophylactic Use of Trihexyphenidyl (Artane) in Schizophrenia and Psychosis: a Critical Review of Literature to Guide for Evidence Based Practice in Zambia

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Prophylactic Use of Trihexyphenidyl (Artane) in Schizophrenia and Psychosis: a Critical Review of Literature to Guide for Evidence Based Practice in Zambia Medical Journal of Zambia, Vol. 46 (2): 133 - 139 (2019) Original Article Prophylactic Use of Trihexyphenidyl (Artane) in Schizophrenia and Psychosis: A Critical Review of Literature to Guide for Evidence Based Practice in Zambia W. A. Sheikh Department of Psychiatry, Livingstone Central Hospital, Livingstone ABSTRACT Conclusion: There is generally no need to start an anticholinergic drugs when a patient is prescribed Background: Anticholinergic drugs are particularly antipsychotics. For patients who are already on used in psychiatric practice to counteract the EPS anticholinergic drugs, discontinuation of these drugs secondary to antipsychotic drugs. Trihexyphenidyl should be considered in patients with stable EPS. (Benzhexol), commonly known as 'Artane' is most Anticholinergic drugs can be considered only in widely used anticholinergic drug in Zambia. It is individuals with significant EPS when dose routinely prescribed as prophylaxis to counteract the reduction and switching strategies have proven side-effects in patients taking FGA. In anecdotal ineffective, or when the side effects are acute or experience the abuse of artane is very common severe. among mental patients as well as in the general public in Zambia. This article reviews the literature INTRODUCTION about psychiatric use, mechanism of action and abuse potential of trihexyphenidyl. Schizophrenia is one of the most serious and debilitating psychiatric illness with life time Objective: This review aim to critically review the prevalence of about 1% round the globe.1,2 It is literature about use of trihexyphenidyl to guide characterized by positive, negative, cognitive and whether it is justified to use this drug for prophylaxis affective symptoms. Since the introduction of to counteract the side-effects of antipsychotics in chlorpromazine in 1952, antipsychotic drugs Zambia. represent the mainstay of the pharmacological treatment for psychosis and schizophrenia.2,3,4 Exact Methodology: Literature search was conducted pathophysiological mechanisms underlying using MEDLINE via PubMed (from 1970- schizophrenia are unknown but consistent evidence 2018).Initially broad search was undertaken to find points to an increased subcortical presynaptic controlled studies, case reports and review articles dopamine neurotransmission. 2 , 5 On this and later some relevant bibliographic articles were neurochemical basis, all antipsychotics are reviewed to find some more studies. dopamine D2 receptor antagonists. By blocking dopaminergic neurotransmission in subcortical Corresponding author: areas, they are capable of producing extra- Waqas Ahmed Sheikh Department of Psychiatry, Livingstone Central Hospital, pyramidal side-effects (EPS), such as Parkinsonism P.O. Box 60091 Livingstone-Zambia Phone number: +260977796947, Key Words: Antipsychotics, Schizophrenia, Trihexyphenidyl, E. mail: [email protected] Zambia 133 Medical Journal of Zambia, Vol. 46 (2): 133 - 139 (2019) (tremor, akinesia and rigidity), akathesia, dystonia OBJECTIVE and tardive dyskinesia (TD), occurring acutely or during chronic treatment.2,4 In general, this This review aim to critically review the literature propensity is more pronounced with the first- about use of trihexyphenidyl to guide whether it is generation antipsychotics (FGA) than with the justified to use this drug for prophylaxis to second generation antipsychotics (SGA).2,6 In the counteract the side-effects of antipsychotics in past 2 decades, SGA replaced FGA as the standard Zambia. treatment for schizophrenia in many parts of the METHODOLOGY world although there is recent evidence indicating no differences in their effectiveness.2,6 In Zambia Literature search was conducted using MEDLINE FGA like haloperidol, chlorpromazine, via PubMed (from 1970-2018) and using the key trifluoperazine, and fluphenazine decanoate are still words: used as first line treatments for psychosis and Trihexyphenidyl, benzhexol, artane, anticholinergic schizophrenia at all public clinics and hospitals. drugs, first and second generation antipsychotics, SGA like risperidone, clozapine etc. are available in schizophrenia, antiparkinsonian drugs, use, and public sector at teaching hospitals as 2nd line misuse. treatments but most of the SGA are available in Initially broad search was undertaken to find private sector. controlled studies, case reports and review articles Anticholinergic drugs are particularly used in and later some relevant bibliographic articles were psychiatric practice to counteract the EPS secondary reviewed to find some more studies. to antipsychotic drugs. 7 , 8 Trihexyphenidyl PHARMACOLOGY OF TRIHEXYPHENIDYL (Benzhexol), commonly known as 'Artane' is most widely used anticholinergic drug in Zambia. Acetylcholine (Ach) is an excitatory Trihexyphenidyl is routinely prescribed as neurotransmitter in the brain and has multiple prophylaxis to counteract the side-effects in patients physiological functions in the nervous system.8 Ach taking FGA. In anecdotal experience the abuse of exerts its effects by binding two major subtypes of artane is very common among mental patients as receptors: the metabotropic muscarinic receptors14 well as in the general public in Zambia. and inotropic nicotinic receptors.15 Anticholinergic abuse has been reported in many Dopamine and Ach have reciprocal relationship with clinical settings particularly in patients with severe each other in the nigrostriatal pathway. Dopamine mental illness, where the prevalence of misuse could normally inhibit Ach release from postsynaptic reach 34%. 7 , 1 1 In a 2008 news report, nigrostriatal cholinergic neurons, thus suppressing 8 “trihexyphenidyl was seen to be used for Ach activity there (Figure 1). recreational purposes among Iraqi soldiers and police, among other prescription drugs. The report states that the drugs were taken to relieve combat stress.”12 Different studies revealed that the purpose of abuse is to achieve a euphoric state and to enhance social skills.13 This article reviews the literature about psychiatric use, mechanism of action and abuse potential of trihexyphenidyl. FIGURE 1, Reciprocal Relationship of Dopamine and Acetylcholine.8 134 Medical Journal of Zambia, Vol. 46 (2): 133 - 139 (2019) If dopamine receptors are blocked by FGA, then On the other hand, trihexyphenidyl also act as a dopamine can no longer suppress Ach release, so potent indirect dopamine agonist.7,16 in the limbic Ach becomes overly active, and produce system, which is a set of interconnected brain EPS8(Figure 2).9 structures including the nucleus accumbens and the ventral tegmental area, involved in motivation, learning, memory and reward. This can in part explain the abuse potential of trihexyphenidyl in both psychiatric and non-psychiatric patients.7 PROPHYLACTIC USE OF TRIHEXYPHENIDYL Anticholinergic agents like trihexyphenidyl have long been considered the treatment and prophylaxis of choice for antipsychotic-induced EPS. The EPS treated with trihexyphenidyl include Parkinsonism (tremors, rigidity& bradykinesia) and acute dystonia.17 Trihexyphenidyl however is known to FIGURE 2, Dopamine, Acetylcholine and D2 worsen TD. 1 8 Xerostomia, blurred vision, Antagonism.9 xerophthalmia, constipation and flushed skin are the 19,20 One compensation for this over activity of Ach is to common side effects of trihexyphenidyl. Delayed block it with anticholinergic agent like micturition, urinary retention and sexual trihexyphenidyl. Thus trihexyphenidyl will dysfunction are occasionally seen.19,20 A more diminish the excess Ach activity caused by removal worrisome effect often seen in aging patients is of dopamine inhibition when dopamine receptors cognitive impairment.20,21Abuse of anticholinergic are blocked by FGA8 (Figure 3).10 drugs like trihexyphenidyl can lead to euphoria and psychosis.19,22 This relieves EPS like Parkinsonism and acute dystonia. This has led to the common strategy of In the patients treated with anticholinergic drugs, the giving trihexyphenidyl along with FGA in order to need for anticholinergic drugs is frequently not reduce EPS. Unfortunately this concomitant use of reassessed and many patients may remain on them trihexyphenidyl doesn't lessen the ability of FGA to for several years or even decades. WHO Heads of cause TD. It also causes the well- known side effects Centers Collaborating in WHO coordinated Studies associated with anticholinergic agents, such as dry on Biological Aspects of Mental Illness (1990) mouth, blurred vision, constipation, urinary issued a consensus statement against the retention and cognitive dysfunction.8 prophylactic use of anticholinergic drugs in patients receiving antipsychotics. 23 They recommended that “anticholinergic use be limited to when Parkinsonism arose and when other measures such as dose reduction or antipsychotic switching have failed.23Switching to lesser EPS-producing antipsychotics such as quetiapine or clozapine is an option that may limit or avoid the use of anticholinergic drugs like trihexyphenidyl in some patients”.23 “The 2009 Schizophrenia Patient Outcomes Research Team (PORT) Treatment 24 FIGURE 3, D2 Antagonism and Anticholinergic Recommendations stated that the prophylactic use Agents.10 of anticholinergic drugs to reduce the incidence of 135 Medical Journal of Zambia, Vol. 46 (2): 133 - 139 (2019) EPS was not warranted in patients treated with SGA, drugs. Desmarais et al in a literature review about but should be evaluated on an individual basis for anticholinergic drugs in 201219, quoted a study by patients treated
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